Quite frequently experimentally measured quantities have to be combined in some way in order to determine some other derived quantity. For example, in order to find the uncertainty in drug concentration of a drug that was measured on a balance of a particular sensitivity and mixed with excipients measured on a balance of same or different sensitivity, the uncertainties in the measured quantities have to be combined appropriately.
In the pharmaceutical industry, the Federal Drug Administration (FDA) approves only dosage forms in which the drug content conforms to the specified one with a very small allowable variation. A limited survey conducted by the Federal Drug Administration, Division of Drug Compliance and Surveillance, on compounded drug products in 2001, showed that 31% of the products failed a standard assay testing, with a range of 59 percent to 89 percent of expected potency.1 In this same survey, the failure rate of commercial drug products was found to be close to 2%. The results of the survey are alarming and undoubtedly they jeopardize the future role of compounding pharmacy as an integral part of the country's modern healthcare system.
As shown in FIG. 1, manufacturers have to choose using whole stock mixture to manufacture excess pharmaceutical dosage forms or just an aliquot to yield exactly the desired quantity of unit dosage forms. Large scale pharmaceutical manufacturers would perhaps prefer route 1, while smaller scale GMP certified manufacturers would perhaps prefer the more economic route 2. The representative dosage form shown here is a tablet, but it could be any other pharmaceutical dosage form, i.e, capsule, powder, suppository, etc.
What we need to understand is that large scale manufactures mix ingredients at quantities large enough to produce thousands or millions of pharmaceutical unit dosage forms for individual patient use. Those ingredients that constitute the mixture or the formula, are measured separately on designated balances of certain sensitivity and subsequently mixed in large blenders for the purpose of producing homogeneous powder mixtures of uniform consistency throughout. Sometimes the whole quantity is used to produce unit dosage forms but sometimes only an aliquot of the stock mixture is used at a time. To correctly calculate the maximum potential error of the drug quantity in the unit dose or finished product one has to account for the error incurred in all measurements at all steps of the manufacturing process and combine these errors appropriately. Errors associated with the measurement of the individual ingredients composing the mixture can be calculated using error propagation theories, whereas errors associated with measurement of the powder mixture can be added together. The resultant overall error is dependent on the particular process used to manufacture the product, that is, use of the aliquot method or use of the whole powder mixture (FIG. 1, route 1 and 2, respectively).
It is important to understand the difference between type of analysis C and D from analysis E (see Application of the Algorithm in “Detailed Description of the Invention” section). The user may wish to use the whole powder mixture prepared to manufacture excess quantity of dosage forms or finished product. The user needs to use the Aliquot concept only if the intention is to produce the exact quantity of individual dosage forms as specified in the formula or prescription. Both methods are acceptable and they share certain advantages and disadvantages. For example, the advantage of the aliquot method is that the user may use the remaining of the stock powder to manufacture a different “strength” dosage forms or dosage forms of different composition. Large-scale manufactures usually prefer manufacturing excess product especially if they know that other orders for this product will arrive in the near future. This way, costly and cumbersome extra cleaning of equipments and rooms utilized to manufacture the particular dosage form is avoided. Another potential advantage of manufacturing excess dosage forms lies in the possible increased stability of the drug in the dosage form as compared to its stability in the bulk powder mixture.
There is currently no method available that determines the error of an ingredient concentration present in a mixture. The present invention relates to a novel approach that combines uncertainties in the measurements of drug and excipients and effectively calculates the maximum potential error of drug concentration in pharmaceutical mixtures.